The goal of this project is to determine if myeloperoxidase (MPO) levels or MPO-generated oxidants in cerebral spinal fluid (CSF) or serum provide an early biomarker for Alzheimer's disease (AD). MPO is an oxidant-generating enzyme which is absent from normal aged brain yet abundant in amyloid plaques in AD brain. Our studies have shown that the human MPO gene is aberrantly expressed in astrocytes in AD brain as well as in our huMPO-APP mouse model. Moreover, in the mouse model, MPO expression occurs at early stages prior to significant plaque deposition. Here we propose to investigate whether huMPO levels in CSF or serum constitute a biomarker for early pathology in the humanized MPO-APP23 mouse model. In collaboration with John Chen we will also investigate whether the presence of MPO activity in the brains of these mice can be imaged using a novel MRI technique. We plan to follow-up our mouse studies with the examination of CSF from AD cases and controls. In collaboration with Boston University AD Center and Sun Health Research Institute, we will examine the levels of MPO and its oxidants in CSF from patients with early to late AD and controls. The findings will reveal if MPO or its oxidant byproducts in CSF or serum provide a biomarker to identify patients at an early stage, prior to appearance of symptoms by which time irreversible damage would have occurred. Such biomarkers would also be valuable as a means to monitor the efficacy of novel therapeutic agents and assess disease progression. PUBLIC HEALTH RELEVANCE: It is important to find biomarkers which allow us to diagnose Alzheimer's disease at early stages, prior to appearance of symptoms at which time irreversible damage has already occurred. CSF or serum MPO or MPO-oxidants may represent an accessible biomarker which would help to differentiate between early AD, vascular dementia, and mild cognitive impairment, and assess disease progression. A more reliable biomarker would also be valuable for monitoring the efficacy of novel therapeutics in human subjects as well as mouse models for AD.